Microfluidic device for the manipulation of a non-magnetic liquid

ABSTRACT

This invention relates to a microfluidic device for the manipulation of a non-magnetic liquid, comprising at least one cell comprising:  
     an enclosure ensuring the confinement of a magnetic liquid ( 5 ), immiscible with the non-magnetic liquid ( 7 ) to be manipulated,  
     magnetic means ( 6 ) associated with the enclosure and permitting local application to the magnetic liquid of a magnetic field whose energy profile has a depression, giving rise to at least one volume for reception of the non-magnetic liquid, by forcing the magnetic liquid back, the magnetic field being displaceable to permit a manipulation of the non-magnetic liquid between means for introduction ( 3 ) and means for evacuation ( 4 ).

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority based on International Patent Application No. PCT/FR02/03511, entitled “Microfluidic Device For The Manipulation Of A Non-Magnetic Liquid” by Olivier Constantin, Patrick Pouteau and Yves Fouillet, which claims priority of French application no. 01 13262, filed on Oct. 15, 2001, and which was not published in English.”

TECHNICAL FIELD OF THE INVENTION

[0002] The invention relates to a microfluidic device for the manipulation of a non-magnetic liquid. Such a device can be used in the field of biochips, in the pharmaceutical industry, and in fine chemistry. It can also be used for the manipulation of dangerous liquids.

DESCRIPTION OF THE PRIOR ART

[0003] Devices using magnetic fluids for the manipulation of small volumes of non-magnetic fluids all depend on a principle of pumping in pre-existing tubes, or tubes formed in a substrate. U.S. Pat. No. 5,005,639 is representative of this principle. In this kind of device, the displacement of the non-magnetic fluid is confined to a single dimension or to a single direction.

[0004] Other devices, such as that described in the international application WO 99/58 245, if they do not have channels with solid walls, permit the displacement of a volume of fluid only along a linear path which is predefined by the structuring of displacement surfaces. The liquid being manipulated can only be displaced in the dimension defined by these paths. Moreover the magnetic control is only envisaged in the case where a magnetic liquid is the subject of the manipulation (blocking of the liquid by magnetic valves). The magnetic liquid is not used to manipulate another, non-magnetic, liquid.

[0005] Active microfluidic devices are already known (valves, pumps, etc.), manufactured by MEMS (Micro-Electro-Mechanical Systems) technologies employing techniques of micro-machining and of assembly of substrates and thin layers. The article “Micro-systems in biomedical applications” by P. DARIO et al., J. Micromech. Microeng. 10 (2000), pages 235-244, may be referred to on this subject. These active microfluidic devices comprise movable mechanical elements which are difficult to produce and have a limited lifetime.

[0006] Furthermore, none of these devices may be wholly reconfigured from one use to another, nor during use.

DESCRIPTION OF THE INVENTION

[0007] In order to remedy the disadvantages of the prior art devices, a reconfigurable active microfluidic device is proposed, using a magnetic liquid to form a wall for a volume of a non-magnetic liquid to be manipulated. This wall is formed by creating a deformation in the volume of magnetic liquid. This deformation enables a non-magnetic liquid, immiscible with the magnetic liquid (or plural non-magnetic liquids, immiscible with the magnetic liquid) to be integrated into the device. This or these non-magnetic liquid(s) may be termed “contained liquid(s)”. It is possible by control of the magnetic means to cause the displacement or the transformation (division, mixing, etc.) of the volume of contained liquid.

[0008] The invention thus has as its object a microfluidic device for the manipulation of a non-magnetic liquid, comprising at least one cell comprising:

[0009] an enclosure ensuring the confinement of a magnetic liquid, immiscible with the non-magnetic liquid to be manipulated,

[0010] means for introduction of the non-magnetic liquid into the enclosure,

[0011] means for evacuation of the non-magnetic liquid from the enclosure,

[0012] magnetic means associated with the enclosure and permitting the local application to the magnetic liquid of a magnetic field, the energy profile of which has a depression giving rise to at least one volume for reception of the non-magnetic liquid, by forcing the magnetic liquid back, said magnetic field being capable of being displaced to permit a manipulation of the non-magnetic liquid between said introduction means and said evacuation means.

[0013] The means for introduction of the non-magnetic liquid may comprise at least one inlet orifice.

[0014] The means for evacuation of the non-magnetic liquid may comprise at least one outlet orifice.

[0015] The magnetic means may comprise at least one permanent magnet and/or at least one fixed or movable electromagnetic element.

[0016] Advantageously, the cell comprises a flat enclosure, constituted from two parallel plates confining the magnetic liquid in the form of a sheet. The magnetic means can be supported by at least one of the two plates and/or integrated with at least one of the two plates. At least one of the plates has its face internal to the cell treated to facilitate the manipulation of the non-magnetic liquid and/or of the magnetic liquid. The magnetic means may comprise a writeable magnetic material. This writeable magnetic material (magnetic tape or disk) may be transformed into a permanent magnet of chosen form by a writing operation of the same type as that used for data storage. This operation may be performed before the assembly of the confinement enclosure or afterward, just before the manipulation. The magnetic means may also comprise at least one matrix of individually addressable and/or switchable electromagnetic elements. They may be fixed or movable.

[0017] According to a first alternative embodiment, the magnetic means comprise at least one tubular permanent magnet with its axis perpendicular to the sheet of magnetic liquid and with its magnetization perpendicular to the sheet of magnetic liquid. The volume for receiving the non-magnetic liquid then corresponds to the depression of magnetic energy existing in the axis of the tubular permanent magnet.

[0018] According to a second alternative embodiment, the magnetic means comprise two mutually parallel magnetized bars, with magnetization perpendicular to the sheet of magnetic liquid. The volume for receiving the non-magnetic liquid then corresponds to the depression of magnetic energy existing between the two bars. This device can furthermore comprise means for conjointly displacing the two magnetized bars between at least a first position and a second position. The means for conjointly displacing the two magnetized bars may cause a displacement by rotation and/or by translation of the two magnetized bars. The two magnetized bars may possess means causing at least one localized restriction of the volume for receiving the non-magnetic liquid, the means for conjointly displacing the two magnetized bars causing, by the displacement of these bars, the propulsion of the non-magnetic liquid contained in the receiving volume.

[0019] The device may comprise at least two adjacent cells, with the non-magnetic liquid evacuation means of the cell communicating with the non-magnetic liquid introduction means of the adjacent cell. Two adjacent cells may have a common plate and thus be superposed.

BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The invention will be better understood, and other advantages and particulars will become apparent, on reading the following description, given by way of non-limiting example, and the accompanying drawings.

[0021]FIG. 1 is a diagram showing an energy profile of a magnetic field used by the present invention,

[0022]FIG. 2 is a partial perspective view of a first microfluidic device for the manipulation of a non-magnetic liquid, according to the invention,

[0023]FIG. 3 is a partial perspective view of a second microfluidic device for the manipulation of a non-magnetic liquid, according to the invention,

[0024]FIG. 4 is a view explaining the functioning of a microfluidic device permitting the projection of a non-magnetic liquid, according to the invention,

[0025]FIG. 5 is a view from above of another microfluidic device for the manipulation of a non-magnetic liquid, according to the invention,

[0026]FIG. 6 is a perspective view of the principal parts of yet another microfluidic device for the manipulation of a non-magnetic liquid, according to the invention.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

[0027]FIG. 1 is a diagram showing an energy profile E_(CM) of a magnetic field as a function of a direction x. Such an energy profile permits the deformation of a magnetic liquid subjected to this magnetic field. The magnetic liquid tends to leave the zone where the energy of the magnetic field is weak, for its periphery, where the energy of the magnetic field is strong, leaving space free for another liquid which is non-magnetic and immiscible with the magnetic liquid. This non-magnetic liquid is then confined by walls of magnetic liquid.

[0028] The magnetic liquids which may be used by the invention are constituted by solid magnetic particles in suspension in a liquid matrix which is aqueous (ionic magnetic liquids) or oily (oily magnetic liquids).

[0029] The non-magnetic liquids which may be manipulated, or contained liquids, are solutions which may or may not contain suspended particles. These particles may be solid (non-magnetic materials), biological (inert or living) or a combination of the two.

[0030] The device according to the invention is reconfigurable because the walls of the containing magnetic liquid can be modified at will, according to a predetermined choice.

[0031] In particular, the volume of magnetic liquid can be delimited by two solid, mutually parallel plates, forming a cell for manipulation of non-magnetic fluids. FIG. 2 is a partial perspective view of such a cell. It shows two flat plates 1 and 2, mutually parallel and spaced apart by a sub-millimeter distance. The cell comprises, for example, an inlet capillary 3 ending perpendicularly on the plate 1 and an outlet capillary 4 parallel to the plane of the cell. The cell is filled with a magnetic liquid 5, immiscible with the fluid to be manipulated. The magnetic liquid 5 forms a sheet. The cell is closed at its periphery by elements which are not shown. The cell is designed to receive a certain quantity of magnetic fluid and to be capable of creating there a receiving volume for non-magnetic fluid. For example, the plates 1 and 2 may be of a material chosen to permit an increase of the internal volume of the cell.

[0032] By creating a magnetic field so as to have a low magnetic field energy in a volume of non-magnetic fluid and a high magnetic field energy outside this volume of non-magnetic fluid, where the magnetic liquid tends to go, confinement of the volume of fluid to be manipulated by a wall of magnetic liquid is obtained.

[0033] As shown in FIG. 2, the magnetic field profile may be obtained by a tubular permanent magnet 6 placed, for example, under the plate 2. A magnetic field energy hole is created in the axis of the tubular magnet, enabling a drop 7 of non-magnetic liquid to be confined by the walls formed by the magnetic liquid 5. By displacing the magnet 6 under the plate 2, the magnetic field energy profile is likewise displaced, as well as the wall of magnetic liquid. The drop 7 can thus be brought, by a desired path, from the inlet capillary 3 to the outlet capillary 4. The displacement of the walls of magnetic liquid can take place in two dimensions and in any direction chosen by the manipulator.

[0034] The magnet 6 can be embodied by a steel tube of 3 mm internal diameter and 10 mm external diameter, placed on a cylindrical magnet of NdFeB, 10 mm in diameter. The magnetic field used is 0.12 T, for example. This magnetic field permits a drop of non-magnetic, immiscible liquid 3 mm in diameter (that is, less than 4 μl) to be displaced in a sheet of magnetic liquid in any direction in the plane of the sheet. The drop of contained liquid is formed under the inlet capillary 3 by pressure, this capillary being connected to a syringe of non-magnetic liquid installed in a syringe pusher. Once the drop is formed, its displacement is controlled magnetically.

[0035] It is then possible to control the displacement of one or more drops, for example containing solid (microspheres, for example) or biological (cells, for example) micro-objects, in suspension in a solution.

[0036]FIG. 3 is a partial sectional view of another device according to the present invention. The cell of the device comprises, as for the foregoing device, two plates 11 and 12 for confinement of a magnetic liquid 15, immiscible with the non-magnetic liquid to be manipulated.

[0037] Two mutually parallel magnetized bars 13 and 14 are disposed under the plate 12. Their magnetization is perpendicular to the plane of the cell. A channel free from magnetic liquid is then formed in the sheet of magnetic liquid above the space comprised between the two bars 13 and 14. This channel is formed when a non-magnetic liquid is caused to circulate. By conjointly displacing the bars 13 and 14 under the plate 12, the walls of magnetic liquid are displaced. A microfluidic pointer is obtained by swinging the channel, for example, from an inlet capillary 16/outlet capillary 17 axis to an inlet capillary 16/outlet capillary 18 axis.

[0038] Different, fixed or movable, configurable microfluidic devices can be envisaged in conformity with the invention, using different, fixed or movable, geometries or configurations of magnets or electromagnets: channels which are rectilinear, curved, with or without restriction, pointing, switching, mixing, etc.

[0039] A restriction of a channel delimited by the walls of a magnetic liquid can be obtained by means of two bars 23 and 24 (see FIG. 4, which shows a restriction seen from above). The bars 23 and 24 have two perpendicular extensions, respectively 27 and 28, which cause a restriction of the channel containing the non-magnetic liquid 25. By displacing the bars 23 and 24, there can be obtained a propulsion of the non-magnetic fluid comprised in the neighborhood of the space defined by these bars.

[0040] The plates delimiting the cell may be chosen such that their walls internal to the cell are chemically or biochemically compatible with the liquids to be manipulated. The same holds for the magnetic liquid. The plates may be of polymer, glass, or silicon, or may comprise thin layers such as those used in microtechnology. The plates of the same cell can be identical or different in nature. They can be constituted by a combination of materials, certain of the materials constituting them also being able to participate in the constitution of the magnetic means. The plates may be rigid or not.

[0041] The displacement of the magnetic liquid or of the contained non-magnetic liquid may be facilitated by controlling the hydrophobic nature of the internal surfaces of the plates, by the control of the nature of its surfaces, for example be depositing a thin layer of an appropriate material or by creating a micro-structured roughness.

[0042] The inlets and outlets of the cells can be connected to other, coplanar or superposed, cells or to a reservoir of magnetic liquid, permitting complex microfluidic devices to be implemented in three dimensions. In particular, two cells may be superposed, their separation being constituted by a plate common to the two cells and capable of being pierced by holes connecting these two cells.

[0043] The inlets and outlets of the cells can be capillaries, pipette cones, or any other assembly generally used in microfluidics.

[0044] The displacement of the contained liquid can be effected in two dimensions and in any direction.

[0045] The invention permits a simplification of microfluidic technology (no engraving of microchannels, no movable solid parts in contact with the non-magnetic liquid) and thus greater reliability. The liquid to be manipulated being contained by the magnetic liquid, there is no problem of evaporation, even for very small volumes. The devices according to the invention permit the manipulation of liquids which do not have particular dielectric properties (case of electro-osmotic pumping).

[0046]FIG. 5 shows, seen from above, an embodiment of the cell of a device according to the invention. This cell comprises an upper plate 31 of machined Plexiglas, 2 mm thick. The lower plate, not visible in the drawing, is a Hybriwell self-adhesive plastic film, generally used in optical microscopy, 170 μm thick, glued to the upper plate 31 by a peripheral glue joint 33, 120 μm thick. The size of the cell is 64 mm×25.5 mm. The facing surfaces of the lower and upper plates are treated to make them hydrophobic.

[0047] The cell of FIG. 5 comprises two inlets 32 and 34 and three outlets 35, 36 and 37 of 400 μm diameter formed in the upper plate 31, into which are glued capillaries (not shown) of external diameter 380 μm and internal diameter 250 μm.

[0048] By placing two magnetized bars 38 and 39 of NdFeB below the cell, there is created by variation of the energy of the magnetic field a channel free from magnetic liquid which is formed between the upper and lower plates by pushing a non-magnetic liquid, immiscible with the magnetic liquid, from an inlet toward an outlet. The magnetization of the bars is perpendicular to the surface of the plates. The magnetic field is about 0.27 T.

[0049] The bars 38 and 39 create, for example, a channel between the inlet 32 and the outlet 36. By rotation around the axis of the inlet 32, the channel may align between the inlet 32 and the outlet 35. By translation, the channel may slide from the direction inlet 32-outlet 36 to the direction inlet 34-outlet 37.

[0050] The non-magnetic liquid can be pushed into the inlet capillary and into the channel by a syringe installed in a syringe pusher.

[0051] Different geometries of microfluidic pointers or switches can be imagined, based on the displacement of permanent magnets, permitting the displacement of channels with liquid walls from one or more inlets toward one or more outlets. FIG. 6 shows a circular pointer with a central inlet 45 and several peripheral outlets 46 formed on the upper plate 41. A sheet of magnetic liquid, not shown, is confined between the upper plate 41 and the lower plate 42. Disposed under the lower plate 42 are two mutually parallel magnetized bars 43 and 44, the magnetization of which is perpendicular to the plane of the cell. The magnetized bars 43 and 44 are conjointly movable in rotation around the axis of the central inlet 45. The conjoint rotation of the magnetized bars 43 and 44 permits the creation of a channel between the central inlet 45 and any one of the outlets 46.

[0052] The device according to the invention can employ a matrix of individually addressable and/or switchable electromagnets. This type of matrix permits a generic, possibly programmable, microfluidic component to be envisaged, which can be configured at will and in which walls of magnetic liquid can be manipulated to create channels of more or less complex form (serpentine, for example), pointers or injectors. The walls of magnetic liquid can also be manipulated for displacing, mixing, or dividing drops of liquid.

[0053] The same device can fulfill one or more of the functions mentioned hereinabove and can be associated with functions of heating, of stimulation (electrical, optical, chemical or biological) or of detection. For example, by bringing the quantity of contained liquid directly beneath a capillary, a reagent may be injected there, or some or all of the contained liquid may be aspirated. The contained liquid may also be brought directly beneath one or more electrodes, to apply an electrical stimulation to it. The contained liquid may also be brought directly beneath a zone of controllable temperature (activation or inhibition of a chemical or biological reaction in a drop of reagent, for example).

[0054] By bringing the contained liquid directly beneath an optical device, an optical signal may be activated or detected, for example by fluorescence, through a window in the cell, transparent to a certain wavelength, or through an optical fiber. 

1. A microfluidic device for the manipulation of a non-magnetic liquid, comprising at least one cell comprising: an enclosure ensuring the confinement of a magnetic liquid, immiscible with the non-magnetic liquid to be manipulated, means for the introduction of the non-magnetic liquid into the enclosure, means for the evacuation of the non-magnetic liquid from the enclosure, magnetic means associated with the enclosure and permitting the local application to the magnetic liquid of a magnetic field whose energy profile has a depression, giving rise to at least one volume for reception of the non-magnetic liquid, by forcing the magnetic liquid back, the magnetic field being displaceable to permit a manipulation of the non-magnetic liquid between said means for introduction and said means for evacuation.
 2. The device according to claim 1, wherein the means for introduction of the non-magnetic liquid comprise at least one inlet orifice.
 3. The device according to claim 1, wherein the means for evacuation of the non-magnetic liquid comprise at least one outlet orifice.
 4. The device according to claim 1, wherein the magnetic means comprise at lest one permanent magnet and/or at least one fixed or movable electromagnetic element.
 5. The device according to claim 1, wherein the cell comprises a flat enclosure, constituted from two parallel plates confining the magnetic liquid in the form of a sheet.
 6. The device according to claim 5, wherein the magnetic means are supported by at least one of the two plates and/or integrated with at least one of the two plates.
 7. The device according to claim 5, wherein at least one of the plates has its face internal to the cell treated to facilitate the manipulation of the non-magnetic liquid and/or of the magnetic liquid.
 8. The device according to claim 6, wherein the magnetic means comprise a writeable magnetic material.
 9. The device according to claim 5, wherein the magnetic means comprise at least one tubular permanent magnet with its axis perpendicular to the sheet of magnetic liquid and its magnetization perpendicular to the sheet of magnetic liquid.
 10. The device according to claim 5, wherein the magnetic means comprise two mutually parallel magnetized bars, with magnetization perpendicular to the sheet of magnetic material.
 11. The device according to claim 10, furthermore comprising means for conjointly displacing the two magnetized bars between at least a first position and a second position.
 12. The device according to claim 11, wherein the means for conjointly displacing the two magnetized bars cause a displacement by rotation and/or by translation of the two magnetized bars.
 13. The device according to claim 11, wherein the two magnetized bars possess means causing at least one localized restriction of the receiving volume for the non-magnetic liquid, the means for conjointly displacing the two magnetized bars causing, by the displacement of these bars, the propulsion of the non-magnetic liquid contained in the receiving volume.
 14. The device according to claim 1, comprising at least two adjacent cells, means for evacuation of the non-magnetic liquid from one cell communicating with means for introduction of the non-magnetic liquid of the adjacent cell.
 15. The device according to claim 14, wherein two adjacent cells possess a common plate.
 16. The device according to claim 6, wherein the magnetic means comprise at least one matrix of electromagnetic elements which are individually addressable and/or switchable. 